Cefamandole is a cephalosporin antibiotic which is useful for combating infectious diseases such as enterobacter infections as disclosed in U.S. Pat. No. 3,903,278. Cefamandole is 7-(D-mandelamido)-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl- 3-cephem-4-carboxylic acid and was first disclosed by Ryan in U.S. Pat. No. 3,641,021, Example 5. The process for making cefamandole by acylating "tetrazole nucleus," 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, with D-anhydro O-carboxymandelic acid is described by Greene in U.S. Pat. No. 3,840,531. The silylation of a cephalosporin nucleus is described by Jackson in U.S. Pat. No. 3,671,449. Jackson also describes the acylation of a silylated cephalosporin nucleus in U.S. Pat. No. 3,694,437. German Offenlegungsschriff 2522997 (Derwent 81950W/50) discloses 7-(D-.alpha.-hydroxyphenylacetamido)- 3-(6-hydroxypyridazin-3-yl or tetrazolo[4,5-b]-pyridazin-6-yl)thiomethyl- 3-cephem-4-carboxylic acid compounds which are protected on the .alpha.-hydroxyl and carboxylic acid functions. The silylated compounds are merely mentioned as incidental intermediates to the final products. Their preparation or properties are not expressly described in the disclosure.
Cefamandole or its sodium salt in crude form are extremely difficult to purify by recrystallization. Therefore, a practical method of purification is necessary to provide the purity required for pharmaceutical preparations. Crystalline sodium cefamandole can be obtained from cefamandole acid provided the acid is in a pure state.
The use of silyl groups as protecting groups which can be easily removed is widely recognized in the art. However, silylated cephalosporin compounds are generally so unstable that relatively few of them have been characterized as such.
It is a purpose of this invention to provide a stable crystalline cefamandole silyl derivative which is readily converted to cefamandole acid of excellent purity. By the process of this invention crude lots of cefamandole can be converted to the silyl derivative or the silyl derivative can be prepared ab initio by silylation of the cephalosporin tetrazole nucleus followed by acylation with anhydro O-carboxymandelic acid.
The reagents used in the processes of this invention are either commercially available or described in the literature. Both N-trimethylsilylacetamide (MSA) and N,O-bis(trimethylsilyl)acetamide (BSA) are commercially available. The preparation of the acylating agent D-anhydro-O-carboxymandelic acid, ##STR1## is described by Greene in U.S. Pat. No. 3,840,531, Example V.